The use of fluoride as a cariostatic agent in dentistry is well established, and, as a result, its use in multiple delivery systems (dentifrices, mouthrinses, gels, pediatric supplements, dental materials) is steadily increasing with a decreasing prevalence of dental caries being reported in many countries. However, present knowledge of the detrimental effects of fluoride is incomplete, and, as its use increases, there is a growing need to clearly establish what levels and conditions of fluoride exposure, if any, may cause toxic effects. There is increasing scientific information suggesting that fluoride can cause a variety of genotoxic effects which may contraindicate its widespread use in caries prevention. Most previous investigations have used very high, non-physiological doses of fluoride and have based conclusions on the results of only a single test procedure. As a result, there is currently a great deal of confusion and contradiction regarding the genotoxic effects and mutagenic potential of fluoride. Because of this, our laboratory has conducted preliminary studies in which a complementary series of mutagenic test procedures were used to investigate the genotoxic effects of acute fluoride exposure; we propose now to extend these methodologies to study chronic fluoride exposure. Three established in vivo mutagenicity tests will be used to: 1) observe the influence of chronic fluoride treatment on the structure of chromosomes in polychromatic erythrocytes (Micronucleus Test); 2) study the fluoride effects on germ cell morphology of mice during chronic exposure (Sperm Abnormality Test); and 3) determine the effect of chronic fluoride on the specific aberration of chromatid crossover (Sister Chromatid Exchange studies). The ultimate goal of this proposed study is to establish conclusive evidence regarding genotoxic results of chronic fluoride exposure, to determine the nature of any genotoxic effects, and to relate the significance of these effects to the increasing prophylactic and therapeutic uses of fluoride in dentistry.